Project Summary This project builds on our novel finding that topically applied engineered nanomaterials (ENMs) can modulate allergic immune responses in skin. Using a contact hypersensitivity (CHS) mouse model we discovered that some ENMs suppress skin inflammation which is therapeutically relevant and others exacerbate allergic symptoms suggesting an increased hazard for cutaneous ENM exposure particularly for individuals whom suffer with allergic contact dermatitis (ACD). In fact, 15-20% of the US population is diagnosed with ACD which accounts for 95% of reported occupational skin disease and is the third most common reason patients visit a dermatologist. With the expanding industrial and consumer use of ENMs there is a growing risk that individuals with ACD may simultaneously come into skin contact with environmental allergens or chemical sensitizers and ENMs through use of nano- enabled products or from occupational exposures. The primary goal of this project is to understand the cellular and molecular mechanisms of how ENMs modulate allergic skin immune responses for which little is currently understood. We have defined an early time window of action within which ENMs exert their effects and our data suggests an important connection with mast cells (MCs). The central hypothesis of this project is that ENMs exert immunomodulatory effects in skin allergic responses by altering early MC activation. We will examine how ENMs alter the mechanisms of MC activation and their cross talk with other epidermal cell types using innovative live mouse intravital imaging and common techniques in novel ways. A panel of in vitro assays are proposed to further examine if ENMs exert a direct effect on MCs or act indirectly by altering paracrine signals generated by other epidermal cell types thereby suppressing or exacerbating the CHS elicitation response. This project will generate knowledge needed to assess the risk/benefit of unintended/intended ENM skin exposure and generate novel approaches for preventing allergic skin inflammation.